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Restoration of mutant hERG stability by inhibition of HDAC6
https://repository.lib.tottori-u.ac.jp/records/7264
https://repository.lib.tottori-u.ac.jp/records/7264b53c59ee-761d-4a07-9e2b-1940f152a56a
| 名前 / ファイル | ライセンス | アクション |
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jmcc115_158.pdf (567.9 kB)
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| Item type | 学術雑誌論文 / Journal Article(1) | |||||||||||
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| 公開日 | 2021-11-24 | |||||||||||
| タイトル | ||||||||||||
| タイトル | Restoration of mutant hERG stability by inhibition of HDAC6 | |||||||||||
| 言語 | en | |||||||||||
| 言語 | ||||||||||||
| 言語 | eng | |||||||||||
| キーワード | ||||||||||||
| 主題 | hERG | |||||||||||
| キーワード | ||||||||||||
| 主題 | HDAC6 | |||||||||||
| キーワード | ||||||||||||
| 主題 | Acetylation | |||||||||||
| キーワード | ||||||||||||
| 主題 | Ubiquitination | |||||||||||
| キーワード | ||||||||||||
| 主題 | LQT2 | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題 | hERG | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題 | HDAC6 | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題 | Acetylation | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題 | Ubiquitination | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題 | LQT2 | |||||||||||
| 資源タイプ | ||||||||||||
| 資源タイプ | journal article | |||||||||||
| 著者 |
李, 佩俐
× 李, 佩俐× 倉田, 康孝× Mahati, Endang× 二宮, 治明× 檜垣, 克美× 森川, 久未× 白吉, 安昭
WEKO
3385
× 久留, 一郎× Kurata, Yasutaka× Mahati, Endang× Taufiq, Fikri× Horie, Minoru |
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| 著者所属（英） | ||||||||||||
| 言語 | en | |||||||||||
| 値 | Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University | |||||||||||
| 著者所属（英） | ||||||||||||
| 言語 | en | |||||||||||
| 値 | Department of Physiology II, Kanazawa Medical University | |||||||||||
| 著者所属（英） | ||||||||||||
| 言語 | en | |||||||||||
| 値 | Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University | |||||||||||
| 著者所属（英） | ||||||||||||
| 言語 | en | |||||||||||
| 値 | Department of Biological Regulation, Tottori University | |||||||||||
| 著者所属（英） | ||||||||||||
| 言語 | en | |||||||||||
| 値 | Research Center for Bioscience and Technology, Tottori University | |||||||||||
| 著者所属（英） | ||||||||||||
| 言語 | en | |||||||||||
| 値 | Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University | |||||||||||
| 著者所属（英） | ||||||||||||
| 言語 | en | |||||||||||
| 値 | Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University | |||||||||||
| 著者所属（英） | ||||||||||||
| 言語 | en | |||||||||||
| 値 | Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University | |||||||||||
| 著者所属（英） | ||||||||||||
| 言語 | en | |||||||||||
| 値 | Department of Cardiovascular Medicine, Shiga University of Medical Science | |||||||||||
| 著者所属（英） | ||||||||||||
| 言語 | en | |||||||||||
| 値 | Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University | |||||||||||
| 抄録 | ||||||||||||
| 内容記述タイプ | Other | |||||||||||
| 内容記述 | The human ether-a-go-go-related gene (hERG) encodes the α subunit of a rapidly activating delayed-rectifier potassium (IKr) channel. Mutations of the hERG cause long QT syndrome type 2 (LQT2). Acetylation of lysine residues occurs in a subset of non-histone proteins and this modification is controlled by both histone acetyltransferases and deacetylases (HDACs). The aim of this study was to clarify effects of HDAC(s) on wild-type (WT) and mutant hERG proteins. WThERG and two trafficking-defective mutants (G601S and R752W) were transiently expressed in HEK293 cells, which were treated with a pan-HDAC inhibitor Trichostatin A (TSA) or an isoform-selective HDAC6 inhibitor Tubastatin A (TBA). Both TSA and TBA increased protein levels of WThERG and induced expression of mature forms of the two mutants. Immunoprecipitation showed an interaction between HDAC6 and immature forms of hERG. Coexpression of HDAC6 decreased acetylation and, reciprocally, increased ubiquitination of hERG, resulting in its decreased expression. siRNA against HDAC6, as well as TBA, exerted opposite effects. Immunochemistry revealed that HDAC6 knockdown increased expression of the WThERG and two mutants both in the endoplasmic reticulum and on the cell surface. Electrophysiology showed that HDAC6 knockdown or TBA treatment increased the hERG channel current corresponding to the rapidly activating delayed-rectifier potassium current (IKr) in HEK293 cells stably expressing the WT or mutants. Three lysine residues (K116, K495 and K757) of hERG were predicted to be acetylated. Substitution of these lysine residues with arginine eliminated HDAC6 effects. In HL-1 mouse cardiomyocytes, TBA enhanced endogenous ERG expression, increased IKr, and shortened action potential duration. These results indicate that hERG is a substrate of HDAC6. HDAC6 inhibition induced acetylation of hERG which counteracted ubiquitination leading its stabilization. HDAC6 inhibition may be a novel therapeutic option for LQT2. | |||||||||||
| 書誌情報 |
Journal of Molecular and Cellular Cardiology en : Journal of Molecular and Cellular Cardiology 巻 115, p. 158-169, 発行日 2018-02-28 |
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| 出版者 | ||||||||||||
| 出版者 | Elsevier | |||||||||||
| ISSN | ||||||||||||
| 収録物識別子タイプ | ISSN | |||||||||||
| 収録物識別子 | 00222828 | |||||||||||
| DOI | ||||||||||||
| 関連タイプ | isVersionOf | |||||||||||
| 識別子タイプ | DOI | |||||||||||
| 関連識別子 | 10.1016/j.yjmcc.2018.01.009 | |||||||||||
| 権利 | ||||||||||||
| 権利情報 | © 2018 Elsevier Ltd. All rights reserved. | |||||||||||
| 情報源 | ||||||||||||
| 関連名称 | Li, Peili. Kurata, Yasutaka. Endang, Mahati. et al. Restoration of mutant hERG stability by inhibition of HDAC6. Journal of Molecular and Cellular Cardiology. 115. 158-169. 2018. | |||||||||||
| 関連サイト | ||||||||||||
| 識別子タイプ | URI | |||||||||||
| 関連識別子 | https://www.sciencedirect.com/science/article/pii/S002228281830018X | |||||||||||
| 関連名称 | https://www.sciencedirect.com/science/article/pii/S002228281830018X | |||||||||||
| 著者版フラグ | ||||||||||||
| 出版タイプ | AM | |||||||||||
